The present invention relates to a tricyclic compound effective for inhibiting sPLA2-mediated fatty acid release.
sPLA2 (secretory phospholipase A2) is an enzyme that hydrolyzes membrane phospholipids and has been considered to be a rate-determining enzyme that governs the so-called arachidonate cascade where arachidonic acid, the hydrolysis product, is the starting material. Moreover, lysophospholipids that are produced as by-products in the hydrolysis of phospholipids have been known as important mediators in cardiovascular diseases. Accordingly, in order to normalize excess functions of the arachidonate cascade and the lysophospholipids, it is important to develop compounds which inhibit the liberation of sPLA2-mediated fatty acids (for example, arachidonic acid), namely, compounds which inhibit the activity or production of sPLA2. Such compounds are useful for general treatment of symptoms, which are induced and/or sustained by an excess formation of sPLA2, such as septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, cerebral apoplexy, cerebral infarction, inflammatory colitis, psoriasis, cardiac insufficiency, cardiac infarction, and so on. The participation of sPLA2 is considered to be extremely wide and, besides, its action is potent.
Examples of sPLA2 inhibitors include compounds described in EP-620214 (JP Laid-Open No. 010838/95, U.S. Pat. No. 5,578,634), EP-620215 (JP Laid-Open No. 025850/95, U.S. Pat. No. 5,684,034), EP-675110 (JP Laid-Open No. 285933/95, U.S. Pat. No. 5,654,326), WO 96/03120 (JP Laid-Open No. 505336/98), WO 96/03376 (JP Laid-Open No. 503208/98, U.S. Pat. No. 5,641,800), WO 96/03383 (JP Laid-Open No. 505584/98), WO 97/21664 (EP-779271), WO 97/21716 (EP-779273), WO 98/18464 (EP839806), WO98/24437(EP846687), WO98/24756, WO98/24794, WO98/25609, WO99/51605, WO99/59999 and the like, or parabromophenacylbromide, mepacrine, manoaride, theilocien A and the like.
The object of the present invention is to provide tricyclic compounds having sPLA2 inhibitory activity and being useful for treatment or prevention of inflammatory diseases.
The present invention relates to I) a compound represented by the formula (I): 
wherein R1 is (a) C1 to C20 alkyl, C2 to C20 alkenyl, C2 to C20 alkynyl, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each substituted independently with at least one group selected from non-interfering substituents, or (c) xe2x80x94(L1)xe2x80x94R5 wherein L1 is a divalent linking group of 1 to 18 atom(s) selected from hydrogen atom(s), nitrogen atom(s), carbon atom(s), oxygen atom(s), and sulfur atom(s), and R5 is a group selected from the groups (a) and (b);
R2 is a group represented by the formula: 
wherein R18 and R19 are independently a hydrogen atom, C1 to C3 alkyl or a halogen; G1 and G2 are independently an oxygen atom or a sulfur atom; and G3 is xe2x80x94NH2 or xe2x80x94NHNH2;
Q1 is a nitrogen atom or Cxe2x80x94R4;
one of R3 and R4 is xe2x80x94(L2)-(acidic group) wherein L2 is an acid linker having an acid linker length of 1 to 5 and the other is a hydrogen atom, provided that when Q1 is nitrogen, R3 is xe2x80x94(L2)-(acidic group) wherein L2 and acidic group are as defined above;
R21 and R22 are independently a hydrogen atom, C1 to C6 alkyl, aryl, a halogen or aralkyl;
X is xe2x80x94CR23R24xe2x80x94, O, or S, wherein R23 and R24 are independently a hydrogen atom or C1 to C6 alkyl;
Y is a bond or xe2x80x94CR25R26xe2x80x94, wherein R25 and R26 are independently a hydrogen atom or C1 to C6 alkyl;
Z is CHRA, CRA, N, or NRBxe2x80x94, wherein RA is a hydrogen atom, alkyloxycarbonyl, or carboxy; RB is a hydrogen atom or acyl;
a broken line ( - - - ) represents the presence or absence of a bond,
its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
In more detail, the present invention relates to II)-XIV).
II) A compound represented by the formula (II): 
wherein R2, R21, R22, X, Y, Z, and - - - are as defined above;
R6 is xe2x80x94(CH2)mxe2x80x94R9 wherein m is an integer from 0 to 6, and R9 is (d) a group represented by the formula: 
wherein a, c, e, n, q, t and v are independently an integer from 0 to 2; R10 and R11 are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, optionally substituted phenyl, and C1 to C10 haloalkyl; xcex1 is an oxygen atom or a sulfur atom; xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94; xcex3 is an oxygen atom or a sulfur atom; b is an integer from 0 to 3; d is an integer from 0 to 5; f, p, and w are independently an integer from 0 to 5; r is an integer from 0 to 7; and u is an integer from 0 to 4, or R9 is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, phenyl, and a halogen; Q2 is a nitrogen atom or Cxe2x80x94R8;
one of R7 and R8 is xe2x80x94(L3)xe2x80x94R12 wherein L3 is represented by the formula: 
wherein M is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R15)xe2x80x94, or xe2x80x94Sxe2x80x94; R13 and R14 are independently a hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or a halogen, and R15 is C1 to C6 alkyl; and R12 is represented by the formula: 
wherein R16 is a hydrogen atom, a metal, or C1 to C10 alkyl, R17 is independently a hydrogen atom or C1 to C10 alkyl; R35 is C1-C5 alkyl or phenyl; h is an integer from 1 to 8; and the other is hydrogen atom;
provided that R7 is xe2x80x94(L3)xe2x80x94R12, wherein L3 and R12 are as defined above, when Q2 is a nitrogen atom,
its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another. When R10 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.
xe2x80x94CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
III) A compound, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as described in above I) or II), wherein said R1 and R6 are represented by the formula: 
wherein R10, R11, b, d, f, p, r, u, w, xcex1, xcex2, and xcex3 are as defined above.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another. When R10 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.
xe2x80x94CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
IV) A compound, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as described in any one of I) to III), wherein said R1 and R6 are represented by the formula: 
wherein R10, R11, p, u, and w are as defined above.
When the above p, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another.
V) A compound, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as described in any one of I) to IV), wherein said R3 and R7 are xe2x80x94Oxe2x80x94(CH2)gxe2x80x94COOH (g is an integer from 1 to 6).
VI) A compound, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as described in any one of I) to V), wherein said R2 is xe2x80x94COCONH2.
VII) A compound, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as described in any one of I) to VI), wherein said both R21 and R22 are hydrogen atoms.
VIII) A compound represented by the formula (III): 
wherein R10, X, Y, Z, g, and - - - are as defined above, Q3 is a nitrogen atom, or CH,
its prodrug, their pharmaceutically acceptable salt, or solvate thereof.
IX) A compound, its prodrug, their pharmaceutically acceptable salt, or solvate thereof as described in any one of I) to VIII), wherein said (X, Y, Z) is (CH2, CH2, CH), (CH2, CH2, CH2), (CH2, CH2, NRB), (S, single bond, CRA), or (S, single bond, CH), wherein RA and RB are as defined above.
X) A pharmaceutical composition containing a compound as described in any one of I) to IX) as an active ingredient.
XI) A pharmaceutical composition as described in X), which is for inhibiting sPLA2.
XII) A pharmaceutical composition as described in X), which is for treatment or prevention of inflammatory diseases.
XIII) Use of a compound of any one of I) to IX) for preparation of a pharmaceutical composition for treating inflammatory diseases.
XIV) A method for treating a mammal, including a human, to alleviate the pathological effects of inflammatory diseases, which comprises administration to said mammal of a compound as described in any one of I) to IX) in a pharmaceutically effective amount.
In the present specification, the term xe2x80x9calkylxe2x80x9d employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms. An example of the alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, n-pentadecanyl, n-hexadecanyl, n-heptadecanyl, n-octadecanyl, n-nonadecanyl, n-eicosanyl and the like.
The term xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms in the present specification means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one double bond. An example of the alkenyl includes vinyl, allyl, propenyl, crotonyl, isopentenyl, a variety of butenyl isomers and the like.
The term xe2x80x9calkynylxe2x80x9d used in the present specification means a straight or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one triple bond. The alkynyl may contain (a) double bond(s). An example of the alkynyl includes ethynyl, propynyl, 6-heptynyl, 7-octynyl, 8-nonynyl and the like.
The term xe2x80x9ccarbocyclic groupxe2x80x9d used in the present specification means a group derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered, preferably 5 to 10 membered, and more preferably 5 to 7 membered organic nucleus whose ring forming atoms (other than hydrogen atoms) are solely carbon atoms. A group containing two to three of the carbocyclic group is also included in the above stated group. An example of typical carbocyclic groups includes (f) cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); cycloalkenyl (such as cyclobutylenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl); phenyl, naphthyl, norbornyl, bicycloheptadienyl, indenyl, stilbenyl, terphenylyl, phenylcyclohexenyl, acenaphthyl, anthoryl, biphenylyl, bibenzylyl, and a phenylalkylphenyl derivative represented by the formula: 
wherein x is an integer from 1 to 8.
The term xe2x80x9cheterocyclic groupxe2x80x9d used in the present specification means a group derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nucleus having 5 to 14 ring atoms and containing 1 to 3 hetcro atoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom. An example of the heterocyclic group includes pyridyl, pyrrolyl, furyl, benzofuryl, thienyl, benzothienyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, puridinyl, dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl and the like.
Preferred carbocyclic and heterocyclic groups in R1 are (g) a group represented by the formula: 
wherein v is an integer from 0 to 2; R10 and R11 are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, optionally substituted phenyl, and C1 to C10 haloalkyl, xcex1 is an oxygen atom or a sulfur atom, xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94; xcex3 is an oxygen atom or a sulfur atom; b is an integer from 0 to 3, d is an integer from 0 to 4; f, p, and w are an integer from 0 to 5; r is an integer from 0 to 7, and u is an integer from 0 to 4. When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R10 or R11 may be different from one another. When R10 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group. xe2x80x94CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
A more preferable example includes (h) a group represented by the formula: 
wherein R10, R11, xcex1, xcex2, and xcex3 are the same as defined above, and y is 0 or 1. When R10 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group. xe2x80x94CH2xe2x80x94 and xe2x80x94(CH2)2xe2x80x94 in xcex2 may be substituted with R10.
The term xe2x80x9cnon-interfering substituentxe2x80x9d in the present specification means a group suitable for substitution of group (a) (e.g., xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d xe2x80x9ccarbocyclic groupxe2x80x9d and xe2x80x9cheterocyclic groupxe2x80x9d) in R1 on tricyclic compound represented by the formula (I). An example of the non-interfering substituents includes C1 to C10 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C7 to C12 aralkyl (such as benzyl and phenethyl), C7 to C12 alkaryl, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C1 to C10 alkyloxy, C1 to C6 alkyloxy C1 to C6 alkyl (such as methyloxymethyl, ethyloxymethyl, methyloxyethyl, and ethyloxyethyl), C1 to C6 alkyloxy C1 to C6 alkyloxy (such as methyloxymethyloxy and methyloxyethyloxy), C1 to C6 alkylcarbonyl (such as methylcarbonyl and ethylcarbonyl), C1 to C6 alkylcarbonylamino (such as methylcarbonylamino and ethylcarbonylamino), C1 to C6 alkyloxyamino (such as methyloxyamino and ethyloxyamino), C1 to C6 alkyloxyaminocarbonyl (such as methyloxyaminocarbonyl and ethyloxyaminocarbonyl), mono or di C1 to C6 alkylamino (such as methylamino, ethylamino, dimethylamino, and ethylmethylamino), C1 to C10 alkylthio, C1 to C6 alkylthiocarbonyl (such as methylthiocarbonyl and ethylthiocarbonyl), C1 to C6 alkylsulfinyl (such as methylsulfinyl and ethylsulfinyl), C1 to C6 alkylsulfonyl (such as methylsulfonyl and ethylsulfonyl), C2 to C6 haloalkyloxy (such as 2-chloroethyloxy and 2-bromoethyloxy), C1 to C6 haloalkylsulfonyl (such as chloromethylsulfonyl and bromomethylsulfonyl), C1 to C10 haloalkyl, C1 to C6 hydroxyalkyl (such as hydroxymethyl and hydroxyethyl), C1-C6 alkyloxycarbonyl (such as methyloxycarbonyl and ethyloxycarbonyl), xe2x80x94(CH2)z-Oxe2x80x94(C1 to C6 alkyl), benzyloxy, aryloxy (such as phenyloxy), arylthio (such as phenylthio), xe2x80x94(CONHSO2R20), formyl, amino, amidino, halogen, carbamyl, carboxyl, carbalkyloxy, xe2x80x94(CH2)z-COOH (such as carboxymethyl, carboxyethyl, and carboxypropyl), cyano, cyanoguanidino, guanidino, hydrazido, hydrazino, hydroxy, hydroxyamino, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, carbonyl, carbocyclic groups, heterocyclic groups and the like, wherein z is an integer from 1 to 8 and R20 is C1 to C6 alkyl or aryl.
Preferable are halogens, C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, and C1 to C6 haloalkyl as the xe2x80x9cnon-interfering substituentxe2x80x9d in the R1. More preferable are halogens, C1 to C3 alkyl, C1 to C3 alkyloxy, C1 to C3 alkylthio, and C1 to C3 haloalkyl.
These groups may be substituted by at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C2 to C6 haloalkyloxy, C1 to C6 haloalkyl, and halogens.
The term xe2x80x9chalogenxe2x80x9d in the present specification means fluorine, chlorine, bromine, and iodine.
The term xe2x80x9ccycloalkylxe2x80x9d in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms. An example of the cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term xe2x80x9ccycloalkenylxe2x80x9d in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms and at least one double bond(s). An example of the cycloalkenyl includes 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl and the like.
In the present specification, an example of xe2x80x9calkyloxyxe2x80x9d includes methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy and the like.
In the present specification, an example of xe2x80x9calkylthioxe2x80x9d includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, n-pentylthio, n-hexylthio and the like.
The term xe2x80x9cacidic groupxe2x80x9d in the present specification means an organic group functioning as a proton donor capable of hydrogen bonding when attached to a tricyclic nucleus through a suitable linking atom (hereinafter defined as xe2x80x9cacid linkerxe2x80x9d). An example of the acidic group includes (k) a group represented by the formula: 
wherein R16 is a hydrogen atom, a metal, or C1 to C10 alkyl; each R17 is independently a hydrogen atom or C1 to C10 alkyl; R35 is C1-C5 alkyl or phenyl; h is an integer from 1 to 8. Preferable is (1) xe2x80x94COOH, xe2x80x94SO3H, or P(O)(OH)2. More preferable is (m) xe2x80x94COOH. And preferable is also their ester and prodrug.
The term xe2x80x9cacid linkerxe2x80x9d in the present specification means a divalent linking group represented by a symbol xe2x80x94(L2)xe2x80x94, and it functions to join tricyclic nucleus to an xe2x80x9cacidic groupxe2x80x9d in the general relationship. An example of it includes (n) a group represented by the formula: 
wherein M is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R15)xe2x80x94, or xe2x80x94Sxe2x80x94, and R13 and R14 are independently a hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, carboxy, or halogens, wherein R15 is C1-C6 alkyl and Ph is phenyl. Preferable are (o) xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94N(R15)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94, or xe2x80x94Oxe2x80x94CH((CH2)2Ph)xe2x80x94 wherein R15 is C1 to C6 alkyl and Ph is phenyl. More preferable is (p) xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94Sxe2x80x94CH2xe2x80x94.
In the present specification, the term xe2x80x9cacid linker lengthxe2x80x9d means the number of atoms (except for hydrogen atoms) in the shortest chain of a linking group xe2x80x94(L2)xe2x80x94 which connects tricyclic nucleus with the xe2x80x9cacidic groupxe2x80x9d. The presence of a carbocyclic ring in xe2x80x94(L2)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene and cyclohexane ring in the acid linker counts as two atoms in culculating the length of xe2x80x94(L2)xe2x80x94. A preferable length is 2 to 3.
The term xe2x80x9chaloalkylxe2x80x9d in the present specification means the aforementioned xe2x80x9calkylxe2x80x9d substituted with the aforementioned xe2x80x9chalogenxe2x80x9d at arbitrary position(s). An example of the haloalkyl includes chloromethyl, trifluoromethyl, 2-chloromethyl, 2-bromomethyl and the like.
The term xe2x80x9chydroxyalkylxe2x80x9d in the present specification means the aforementioned xe2x80x9calkylxe2x80x9d substituted with hydroxy at arbitrary position(s). An example of the hydroxyalkyl includes hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. In this case, hydroxymethyl is preferable.
In the present specification, the term xe2x80x9chaloalkylxe2x80x9d in xe2x80x9chaloalkyloxyxe2x80x9d is the same as defined above. An example of it includes 2-chloroethyloxy, 2-trifluoroethyloxy, 2-chloroethyloxy and the like.
The term xe2x80x9carylxe2x80x9d in the present specification means a monocyclic or condensed cyclic aromatic hydrocarbon. An example of the aryl includes phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like. Particularly, phenyl and 1-naphthyl are preferred.
The term xe2x80x9caralkylxe2x80x9d in the present specification means a group wherein the aforementioned xe2x80x9calkylxe2x80x9d is substituted with the above-mentioned xe2x80x9carylxe2x80x9d. Such aryl may have a bond at any substitutable position. An example of it includes benzyl, phenethyl, phenylpropyl (such as 3-phenylpropyl), naphthylmethyl (such as 1-naphthylmethyl) and the like.
The term xe2x80x9calkyloxycarbonylxe2x80x9d in the present specification means C1-C6 alkyloxycarbonyl. An example of the alkyloxycarbonyl includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl and the like.
The term xe2x80x9cacylxe2x80x9d in the present specification means C1-C6 alkylcarbonyl or arylcarbonyl opptionally substituted with a halogen and the like. An example of the acyl includes acetyl, trifluoroacetyl, propionyl, benzoyl and the like.
A group of preferable substituents as the R1 to R4 and the X to Z of the compound represented by the formula (I) will be shown in items (A) to (W). Preferable are hydrogen atoms as both the R21 and the R22. Items (f) to (p) are the same group as described above.
As the R1, (A):xe2x80x94(L1)xe2x80x94R9, (B):xe2x80x94(CH2)1-2-(f), (C):xe2x80x94(CH2)1-2-(g), and (D):xe2x80x94(CH2)1-2-(h) are preferred.
As the R2, (E):xe2x80x94COCONH2, xe2x80x94CH2CONH2, or xe2x80x94CH2CO NHNH2, and (F):xe2x80x94COCONH2 are preferred.
As the R3, (G):-(n)-(k), (H):-(n)-(l), (I):-(n)-(m), (J):-(o)-(k), (K):-(o)-(l), (L):-(o)-(m), (M):-(p)-(k), (N):-(p)-(I), and (O):-(p)-(m) are preferred.
As the R4, (P): a hydrogen is preferred.
As the (X,Y,Z) preferable are as the (X,Y,Z), (Q):(CH2,CH2,CH), (CH2,CH2,CH2), (CH2,CH2,NRB), (S, a single bond, CRA), and (S, a single bond, CH), wherein RA and RB are the same as described above.
A preferred group of compounds represented by the formula (I) is shown below.
That is, compounds represented by the formula (I-A): 
(R1,R2,R3,R4,(X,Y,Z))=(A,E,G,P,Q),(A,E,H,P,Q),(A,E,I,P,Q),(A,E,J,P,Q), (A,E,K,P,Q),(A,E,L,P,Q),(A,E,M,P,Q),(A,E,N,P,Q),(A,E,O,P,Q),(A,F,G,P,Q), (A,F,H,P,Q),(A,F,I,P,Q),(A,F,J,P,Q),(A,F,K,P,Q),(A,F,L,P,Q),(A,F,M,P,Q), (A,F,P,Q),(B,E,L,P,Q),(B,E,M,P,Q),(B,E,N,P,Q),(B,E,O,P,Q),(B,F,G,P,Q),(B,F,H,P,Q), (B,F,I,P,Q),(B,F,J,P,Q),(B,F,K,P,Q),(B,F,L,P,Q),(B,F,M,P,Q),(B,F,N,P,Q), (B,F,O,P,Q),(C,E,G,P,Q),(C,E,H,P,Q),(C,E,H,P,Q),(C,E,J,P,Q),(C,E,K,P,Q), (C,E,L,P,Q),(C,E,M,P,Q),(C,E,N,P,Q),(C,E,O,P,Q),(C,F,G,P,Q),(C,F,H,P,Q), (C,F,I,P,Q),(C,F,J,P,Q),(C,F,K,P,Q),(C,F,L,P,Q),(C,F,M,P,Q),(C,F,N,P,Q), (C,F,O,P,Q),(D,E,G,P,Q),(D,E,H,P,Q),(D,E,I,P,Q),(D,E,J,P,Q),(D,E,K,P,Q), (D,E,L,P,Q),(D,E,M,P,Q),(D,E,N,P,Q),(D,E,O,P,Q),(D,F,G,P,Q),(D,F,H,P,Q), (D,F,I,P,Q),(D,F,J,P,Q),(D,F,K,P,Q),(D,F,L,P,Q),(D,F,M,P,Q),(D,F,N,P,Q), and (D,F,O,P,Q)
compounds represented by the formula (I-B): 
R1,R2,R3,(X,Y,Z))=(A,E,G,Q),(A,E,H,Q),(A,E,I,Q), (A,E,J,Q),(A,E,K,Q),(A,E,L,Q),(A,E,M,Q),(A,E,N,Q),(A,E,O,Q),(A,F,G,Q),(A,F,H,Q), (A,F,I,Q),(A,F,J,Q),(A,F,K,Q),(A,F,L,Q),(A,F,M,Q),(A,F,N,Q),(A,F,O,Q),(B,E,G,Q), (B,E,H,Q),(B,E,I,Q),(B,E,J,Q),(B,E,K,Q),(B,E,L,Q),(B,E,M,Q),(B,E,N,Q),(B,E,O,Q), (B,F,G,Q),(B,F,H,Q),(B,F,I,Q),(B,F,J,Q),(B,F,K,Q),(B,F,L,Q),(B,F,M,Q), (B,F,N,Q),(B,F,O,Q),(C,E,G,Q),(C,E,H,Q),(C,E,I,Q),(C,E,J,Q),(C,E,K,Q), (C,E,L,Q),(C,E,M,Q),(C,E,N,Q),(C,E,O,Q),(C,F,G,Q),(C,F,H,Q),(C,F,I,Q), (C,F,J,Q),(C,F,K,Q),(C,F,L,Q),(C,F,M,Q),(C,F,N,Q),(C,F,O,Q),(D,E,G,Q),(D,E, H,Q), (D,E,I,Q),(D,E,J,Q),(D,E,K,Q),(D,E,L,Q),(D,E,M,Q),(D,E,N,Q),(D,E,O,Q), (D,F,G,Q),(D,F,H,Q),(D,F,I,Q),(D,F,J,Q),(D,F,K,Q),(D,F,L,Q),(D,F,M,Q), (D,F,N,Q), and (D,F,O,Q).
The term, xe2x80x9cInflammatory Diseasesxe2x80x9d refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, chronic rheumatism, arterial sclerosis, cereberal hemorrhage, cerebral infarction, cardiac failure, cardiac infarction, psoriasis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter""s syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with xe2x80x9cvasculitic syndromesxe2x80x9d, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec""s granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo gout, non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathrics, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat""s Disease, systemic lupus erythrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.
The term xe2x80x9csolvatexe2x80x9d includes, for example, solvates with organic solvents, hydrates, and the like. In case of forming a hydrate, a questioned compound may be coordinated with a suitable number of water molecules.
The compounds of the invention represented by the formula (I) can be synthesized in accordance with well-known method described in chemical journals. The compounds can also be synthesized in accordance with following the methods A to E. 
wherein R1, R3, R4, R21, R22, R23, R24, R25, R26, RA, G1, and G2 are as defined above;
R27 is the precursor of R1; Hal and Hal2 are halogens.
(Process 1)
A mixture of the compound (V) and the compound (VI) is stirred at 40xc2x0 C. to 90xc2x0 C., preferably 50 to 70xc2x0 C. for 3 to 36 h, preferably 12 to 24 h to give the quaternary salt. To a solution of the obtained quaternary salt in a solvent such as 1,2-dichloroethane or acetonitrile is added a base such as 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) or triethylamine, and the resulting mixture is stirred at 40xc2x0 C. to 90xc2x0 C., preferably 50 to 70xc2x0 C. for 3 to 36 h, preferably 12 to 24 h. After the reaction mixture is subjected to a usual work-up, the compound (VII) can be obtained.
The compound (V) is commercial available or can be synthesized in accordance with the method described in J. Med. Chem., 39, 3636-58(1996). The compound (VI) is commercial available.
(Process 2)
The present process is performed by Friedel-Crafts reaction. To a solution of the compound (VII) in a solvent such as 1,2-dichloroethane or dichloromethane are slowly added R27COHal and a Lewis acid such as AlCl3, SbF5, or BF3 at xe2x88x9278xc2x0 C. to 10xc2x0 C., preferably xe2x88x9220xc2x0 C. to ice bath, and the reaction mixture is stirred at xe2x88x9210xc2x0 C. to 10xc2x0 C., preferably 0xc2x0 C. to 10xc2x0 C. for 5 to 30 min, preferably 10 to 20 min. This reaction is performed without solvent by the dissolving the compound (VII) in R27COHal and in accordance the above-mentioned procedure. After the reaction mixture is subjected to a usual work-up, the compound (VIII) can be obtained (Ref: J. Med. Chem., 39, 3636-58(1996)).
(Process 3)
The present process includes the conversion of the compound (VIII) to the phosphonium salt (IX). A mixture of the compound (VIII) and triphenylphosphine in a solvent such as acetonitrile or toluene is reacted at 80 to 150xc2x0 C., preferably 100 to 120xc2x0 C. for 5 to 72 h, preferably 10 to 24 h to obtain the compound (IX).
(Process 4)
The present process is for constructing the ring by Wittig reaction. To a solution of the compound (IX) in a solvent such as acetonitrile or tetrahydrofuran is added a base such as 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) or potassium t-butoxide and the reaction mixture is reacted at, 20 to 120xc2x0 C., preferably 80 to 100xc2x0 C. for 3 to 24 h, preferably 5 to 10 h to give the compound (X).
(Process 5)
To a solution of the compound (X) in a solvent such as 1,2-dichloromethane or tetrahydrofuran are added Halxe2x80x94C(xe2x95x90G1)xe2x80x94C(xe2x95x90G2)xe2x80x94Hal(e.g., oxalyl chloride) and a base such as N-methylmorpholine or triethylamine, and the reaction mixture is stirred at 30 to 70xc2x0 C., preferably 40 to 60xc2x0 C. for 1 to 10 h, preferably, 3 to 6 h. The reaction mixture is poured into a cold aqueous ammonium solution and the resulting mixture is stirred for 5 to 30 min, preferably, 10 to 20 min. After the reaction mixture is subjected to a usual work-up, the compound (XI) can be obtained.
(Process 6)
The present process includes reduction of the double bond by hydrogenation. To a solution of the compound (XI) in a solvent such as tetrahydrofuran, methanol or ethyl acetate is added Palladium-Carbon catalyst, and the mixture is reacted under hydrogen atmosphere at room temperature for 1 to 5 h, preferably 1 to 2 h to yield the compound (XII). 
wherein R1, R3, R4, R21, R22, R23, R24, R25 R26, R27, RB, G1, G2 and Hal are as defined above; R28 is a protecting group such as benzyloxycarbonyl, or p-methoxybenzyloxycarbonyl)
(Process 1)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 1.
(Process 2)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 2.
(Process 3)
The present process is for constructing a piperidine ring by reductive amination. A solution of the compound (XVII) in a solvent such as tetrahydrofuran or methanol is reacted in the presence of Palladium-Carbon catalyst under hydrogen atmosphere at room temperature for 1 to 10 h, preferably 2 to 5 h to give the compound (XVIII).
(Process 4)
The present step is for N-alkylation or N-acylation. A solution of the compound (XVIII) in tetrahydrofuran or dichloromethane in the presence of RBxe2x80x94Hal and a base such as triethylamine or pyridine is reacted at 20 to 100xc2x0 C., preferably 50 to 80xc2x0 C. for 1 to 24 h, preferably 2 to 5 h to yield the compound (XIX).
(Process 5)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 5. 
wherein R1, R3, R4, R21, R22, G1, G2, and Hal are as defined above; R29 and RA, are alkyl.
(Process 1)
The present step is for constructing a thiophen ring. A solution of the compound (XXI) in a solvent such as ethanol is reacted in the presence of a base such as DBU at 20 to 120xc2x0 C., preferably 50 to 80xc2x0 C. for 1 to 5 h, preferably 1 to 2 h to give the compound (XXII).
The compound (XXI) can be synthesized in accordance with the method described in Bull. Chem. Soc. Jpn., 62, 119 (1989)
(Process 2)
The present process is for hydrolysis of ester to carboxylic acid derivatives followed by decarboxylation.
Hydrolysis of the compound (XXII) in a solvent such as tetrahydrofuran, ethanol, dimethylformamide is carried out in the presence of a base such as sodium hydroxide, potassium hydroxide at 20 to 150xc2x0 C., preferably 50 to 150xc2x0 C. for 1 to 5 h, preferably 1 to 2 h.
Decarboxylation is carried out by the reaction of the above-mentioned carboxylic acid derivatives in solvent such as dimethyl sulfoxide or dimethylformamide at 50 to 200xc2x0 C., preferably 100 to 150xc2x0 C. for 1 to 5 h, preferably 1 to 2 h.
(Process 3)
The present process is for esterification of the carboxyl group of the compound (XXIII). It is carried out by the usual esterification (Ref:Protective groups in organic synthesis (second edition) p227-270).
(Process 4)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 5. 
wherein R1, R3, R4, R21, R22, G1, G2, and Hal are as defined above.
(Process 1)
The present process is for decarboxylation of the carboxylic group of the compound (XXIII). A solution of the compound (XXIII) in a solvent such as quinoline is reacted in the presence of a copper catalyst at 100 to 200xc2x0 C., preferably 120 to 160xc2x0 C. for 15 min to 2 h, preferably 30 min to 1 h to give the compound (XXVI).
(Process 2)
The present process may be carried out in accordance with the same procedure as that of the Method Axe2x80x94Process 5. 
wherein R1, R21, R22, and Hal are as defined above; R30 is C1-C3 alkyl; R31 is C1-C3 alkyl; R32 is C1-C3 alkyl or optionally substituted aryl (e.g., tolyl); R33 is C1-C3 alkyl; R34 is a hydrogen atom or C1-C3 alkyl; n is a integer from 1 to 3; Ms is mesyl.
(Process 1)
The present step is for constructing a pyrrolo[1,2-a]pyrazine ring. A mixture of the compound (XXVIII) and Halxe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94CH2xe2x80x94(CH2)nxe2x80x94CO2R31 is stirred at 40xc2x0 C. to 90xc2x0 C., preferably 50xc2x0 C. to 70xc2x0 C. for 3 to 36 h, preferably 12 to 24 h to give the quaternary salt. To a solution of the obtained quaternary salt in a solvent such as 1,2-dichloroethane or acetonitrile is added a base such as 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) or triethylamine, and the mixture is stirred at 40xc2x0 C. to 90xc2x0 C., preferably 60xc2x0 C. to 80xc2x0 C. for 1 to 10 h, preferably 1 to 5 h. After the reaction mixture is subjected to a usual work-up, the compound (XXIX) can be obtained.
(Process 2)
The present process is for reducing the ester group to alcohol. A solution of the compound (XXIX) in a solvent such as ether or tetrahydrofuran is reacted with a reducing agent such as lithium hydride, lithium aluminum hydride or lithium borohydride at 0xc2x0 C. to 80xc2x0 C., preferably 10xc2x0 C. to 40xc2x0 C. for 30 min to 10 h, preferably 1 h to 5 h to obtain the compound (XXX).
(Process 3)
The present process is for transforming the hydroxy group into xe2x80x94OSO2Me. A solution of the compound (XXX) in a solvent such as dichloromethane or tetrahydrofuran is reacted with methanesulfonyl chloride in the presence of a base such as triethylamine or pyridine at xe2x88x9250xc2x0 C. to 50xc2x0 C., preferably xe2x88x9240xc2x0 C. to 30xc2x0 C. for 10 min to 5 h, preferably 30 min to 2 h to give the compound (XXXI).
(Process 4)
The present process is for transforming xe2x80x94OSO2Me into halogen. A solution of the compound (XXXI) in acetonitrile, acetone or dimethylformamide is reacted with a reagent such as lithium bromide or lithium chloride at 0xc2x0 C. to 100xc2x0 C., preferably 30xc2x0 C. to 60xc2x0 C. for 1 to 10 h, preferably 1 to 5 h to obtain the compound (XXXII).
(Process 5)
The present process is for introducing a substituent at 6-position of the pyrrolo[1,2-a]pyrazine by Friedel-Crafts reaction. To a solution of the compound (XXXII) in a solvent such as dichloromethane or chlorobenzene are added slowly R1COHal and Lewis acid (e.g., AlCl3, SbF5, BF3 and the like) at xe2x88x9278xc2x0 C. to 10xc2x0 C., preferably xe2x88x9220xc2x0 C. to 0xc2x0 C., and the mixture is stirred at xe2x88x9210xc2x0 C. to 10xc2x0 C., preferably, 0xc2x0 C. to 10xc2x0 C. for 30 min to 5 h, preferably 1 h to 3 h. After the reaction mixture is subjected to a usual work-up, the compound (XXIX) can be obtained.
(Process 6)
The present process is for preparing phosphonium salt. A mixture of the compound (XXXIII) and triphenylphosphine and the like in a solvent such as acetonitrile or toluene is reacted at 60xc2x0 C. to 150xc2x0 C., preferably 80xc2x0 C. to 120xc2x0 C. for 5 to 100 h preferably 10 to 70 h to give the compound (XXXIV).
(Process 7)
The present process is for constructing a ring by Wittig reaction. To a solution of the compound (XXXIV) in a solvent such as dichloromethane, acetonitrile, or tetrahydrofuran is added a base such as 1,8-dizabicyclo[5.4.0]-7-undecene (DBU), potassium t-butoxide, and the mixture is reacted at 20xc2x0 C. to 120xc2x0 C., preferably 30xc2x0 C. to 100xc2x0 C. for 1 to 24 h, preferably 3 to 10 h to obtain the compound (XXXV).
(Process 8)
The present process is for transforming the alkyloxy group at 1-position into ketone. An acid such as concentrated hydrochloric acid and the like is added to the compound (XXXV), and the mixture is stirred at 80xc2x0 C. to 150xc2x0 C., preferably 100xc2x0 C. to 120xc2x0 C. for 1 to 5 h, preferably 1 to 3 h. After the resulting product is subjected to a usual work-up, the compound (XXXVI) can be obtained.
(Process 9)
The present process is for transforming the ketone at 1-position into a halogen. A halogenating agent such as phosphorus oxychloride, phenylphosphonic dichloride and the like is added to the compound (XXXVI), and the mixture is stirred at 60xc2x0 C. to 150xc2x0 C., preferably 80xc2x0 C. to 110xc2x0 C. for 10 min to 3 h, preferably 30 min to 1 h. After the resulting product is subjected to an ordinary work-up, the compound (XXXVII) can be obtained.
(Process 10)
The present process is for transforming the halogen at 1-position into a sulfonyl group. To a solution of the compound (XXXVII) in ethanol is added R32SO2Na, and the mixture is refluxed for 10 to 50 h, preferably 24 to 36 h to give the (XXXVIII).
(Process 11)
The present process is for transforming the sulfonyl group at 1-position into alkyloxy group. A suspension of HOCH(R33)CO2R34, sodium hydride and potassium t-butoxide in a solvent such as tetrahydrofuran and the like is stirred at xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 30xc2x0 C. for 15 min to 2 h, preferably 30 min to 1 h. To the solution is added the compound (XXXVIII), and the resulting mixture is stirred at xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to 30xc2x0 C. for 15 min to 5 h, preferably 30 min to 2 h to yield the compound (XXXIX).
(Process 12)
The present process is for introducing a substituent at 5-position. To a solution of the compound (XXXIX) in a solvent such as dichloromethane or tetrahydrofuran are added Halxe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94Hal (Hal is a halogen)(e.g., oxalyl chloride) and a base such as N-methylmorpholine or triethylamine and the reaction mixture is stirred at xe2x88x9230xc2x0 C. to 70xc2x0 C., preferably xe2x88x9220xc2x0 C. to 40xc2x0 C. for 10 min to 10 h, preferably, 10 min to 2 h. The reaction mixture is poured into an aqueous ammonium solution and the resulting mixture is subjected to a usual work-up to give the compound (IL) can be obtained.
(Process 13)
The present process is for hydrolysis. To a solution of the compound (IL) in a solvent such as methanol or tetrahydrofuran is added a base such as sodium hydroxide and the like, and the resulting mixture is stirred at 0xc2x0 C. to 40xc2x0 C., preferably 10xc2x0 C. to 30xc2x0 C. for 0.5 to 6 h, preferably 0.5 to 2 h to give the compound (ILI).
Where a compound of the present invention has an acidic or basic functional group, a variety of salts having higher water solubility and more physiologically suitable properties than those of the original compound can be formed. An example of typical pharmaceutically acceptable salts includes salts with alkali metal and alkaline earth metal such as lithium, sodium, potassium, magnesium, aluminum and the like, but it is to be noted that such pharmaceutically acceptable salts are not limited thereto. A salt is easily manufactured from a free acid by either treating an acid in a solution with a base, or allowing an acid to be in contact with an ion exchange resin. Addition salts of the compounds according to the present invention with relatively non-toxic inorganic bases and organic bases, for example, amine cation, ammonium, and quaternary ammonium derived from nitrogenous bases having a basicity sufficient for forming a salt of the compounds of the present invention are included in the definition of xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d. (e.g., S. M. Berge et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66, 1-19 (1977)) Furthermore, basic groups of a compound according to the present invention are reacted with a suitable organic or inorganic acid to form salts such as acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartarate, borates, bromides, camcyrates, carbonates, chlorides, clubranates, citrates, edetates, edicirates, estrates, ethylates, fluorides, fumarates, gluseptates, gluconates, glutamates, glycolialsanyrates, hexylresorcinates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, laurates, malates, malseates, manderates, mesylates, methylbromides, methylnitrates, methylsulfates, mucates, napcylates, nitrates, oleates, oxarates, palmitates, pantothenates, phosphates, polygalacturonates, salicirates, stearates, subacetates, sucinates, tanates, tartrates, tosylates, trifluoroacetates, trifluoromethanesulfonates, valerates and the like.
In the case where a compound of the present invention has one or more of chiral center(s), it may exist as an optically active member. Likewise, in the case where a compound contains alkenyl or alkenylene, there is a possibility of cis- and trans-isomers. Mixtures of R- and S-isomers as well as of cis- and trans-isomers, and mixtures of R- and S-isomers containing racemic mixture are included in the scope of the present invention. Asymmetric carbon atom may exist also in a substituent such as alkyl group. All such isomers are included in the present invention together with these mixtures. In the case where a specified streoisomer is desired, either it is manufactured by applying a manner which has been well known by those skilled in the art wherein a starting material having an asymmetrical center which has been previously separated is subjected to stereospecific reaction to the starting material, or it is manufactured by preparing a mixture of stereoisomers, and thereafter separating the mixture in accordance with a well-known manner.
Prodrug is a derivative of the compound having a group which can be decomposed chemically or metabolically, and such prodrug is a compound according to the present invention which becomes pharmaceutically active by means of solvolysis or by placing the compound in vivo under a physiological condition. Although a derivative of the compounds according to the present invention exhibits activity in both forms of acid derivative and basic derivative, acid derivative is more advantageous in solubility, tissue affinity, and release control in mammal organism (Bungard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam, 1985). For instance, prodrugs each containing an acid derivative such as an ester which is prepared by reacting a basal acid compound with a suitable alcohol, or an amide which is prepared by reacting a basal acid compound with a suitable amine are well known by those skilled in the art. Simple aliphatic or aromatic esters derived from acid groups contained in the compounds according to the present invention are preferable prodrugs. More preferable is C1-C6 alkyl ester of carboxylic derivatives (e.g., methyl ester, ethyl ester). Double ester such as (acyloxy)alkyl ester or ((alkyloxycarbonyl)oxy)alkyl ester type prodrugs may be optionally manufactured.
The term xe2x80x9cinhibitxe2x80x9d means that release of fatty acid started by sPLA2 decreases significantly by the compounds of the present invention from viewpoint of prevention and treatment of disease. The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means that carriers, diluents, or additives are compatible with other ingredients in a formulation and are not harmful for recipients.
The compounds of the present invention exhibit sPLA2 inhibiting activity as per the description of the experimental examples which will be described hereinafter. Accordingly, when a curatively effective amount of the compounds represented by the formulae (I), (II), and (III), the prodrug derivatives thereof, or their pharmaceutically acceptable salts, or their solvates is administered to any of mammals (including human being), it functions effectively as a curative medicine for diseases of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, cerebral infarction, inflammatory colitis, psoriasis, cardiac failure, cardiac infarction.
The compounds of the present invention may be administered to a patient through a variety of routes including oral, aerosol, rectal, percutaneous, subcutaneous, intravenous, intramuscular, and nasal routes. A formulation according to the present invention may be manufactured by combining (for example, admixing) a curatively effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent. The formulation of the present invention may be manufactured with the use of well-known and easily available ingredients in accordance with a known method.
In case of manufacturing a composition according to the present invention, either active ingredients are admixed with a carrier, or they are diluted with a carrier, or they are contained in a carrier in the form of capsule, sacheier, paper, or another container. In case of functioning a carrier as a diluent, the carrier is a solid, semi-solid, or liquid material which functions as a medium. Accordingly, a formulation according to the present invention may be produced in the form of tablet, pill, powder medicine, intraoral medicine, elixir agent, suspending agent, emulsifier, dissolving agent, syrup agent, aerosol agent (solid in liquid medium), and ointment. Such a formulation may contain up to 10% of an active compound. It is preferred to prepare a compound according to the present invention prior to administration.
Any suitable carrier which has been well known by those skilled in the art may be used for the formulation. In such formulation, a carrier is in the form of solid, liquid, or a mixture of solid and liquid. For instance, a compound of the present invention is dissolved into 4% dextrose/0.5% sodium citrate aqueous solution so as to be 2 mg/ml concentration for intravenous injection. Solid formulation includes powder, tablet, and capsule. Solid carrier consists of one or more of material(s) for serving also as fragrant, lubricant, dissolving agent, suspension, binder, tablet disintegrator, capsule. A tablet for oral administration contains a suitable excipient such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and the like together with a disintegrator such as corn starch, alginic acid and the like and/or a binder such as gelatin, acacia and the like, and a lubricant such as magnesium stearate, stearic acid, talc and the like.
In a powder medicine, a carrier is a finely pulverized solid which is blended with finely pulverized active ingredients. In a tablet, active ingredients are admixed with a carrier having required binding power in a suitable ratio, and it is solidified in a desired shape and size. Powder medicine and tablet contain about 1 to about 99% by weight of the active ingredients being novel compounds according to the present invention. An example of suitable solid carriers includes magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methyl cellulose, sodium carboxymethylcellulose, low-melting wax, and cocoa butter.
An axenic liquid formulation contains suspending agent, emulsifier, syrup agent, and elixir agent. Active ingredients may be dissolved or suspended into a pharmaceutically acceptable carrier such as sterile water, a sterile organic solvent, a mixture thereof and the like. Active ingredients may be dissolved frequently into a suitable organic solvent such as propylene glycol aqueous solution. When finely pulverized active ingredients are dispersed into aqueous starch, sodium carboxylmethylcellulose solution, or suitable oil, the other compositions can be prepared.
The dosage varies with the conditions of the disease, administration route, age and body weight of patient. In the case of oral administration, the dosage can generally be between 0.01 to 50 mg/kg/day for adult.